by Dr. C.H. Weaver M.D. updated 6/2019
PARP Inhibitors are increasingly used to treat women with ovarian or breast cancer with specific genomic defects that prevent them from repairing DNA which results in cancer. Approximately 1 in 4 men with prostate cancer appear to have similar defects in DNA repair and can benefit from treatment with a PARP Inhibitor. Doctors reported at the 2019 American Society of Clinical Oncology annual meeting that the PARP Inhibitor Lynparza delayed progression of prostate cancer for a median of 8.3 months and 35% of men with refractory cancer remained free of progression for more than a year.
About Lynparza (olaparib)
Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor. The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth. PARP inhibitors have anticancer activity in a number of cancers including selected patients with ovarian, fallopian tube, or primary peritoneal cancer, pancreatic, breast, and prostate cancer.
Lynparza was the world’s first drug to reach the market targeted against inherited cancer mutations, and was found to benefit as many as a third of patients with prostate cancer, including many who did not inherit cancer genes but whose cancers had acquired defects in DNA repair according to initial study results released in the New England Journal of Medicine in 2015.
In that trial, 49 men with treatment-resistant, advanced prostate cancer received Lynparza, and 16 of them (33%) responded, as defined by a set of clinical criteria. Lynparza stopped prostate cancer growth, generating lasting falls in prostate specific antigen (PSA) levels, falls in circulating cancer cell counts in the blood, and radiological responses on CT scans and MRI.
The clinical trial found that up to 30% of men with advanced prostate cancer with defects in their systems for repairing DNA detected by genomic testing – and that these responded particularly well to Lynparza.
The results of the trial led to the TOPARP-B clinical trial in which only men whose prostate cancers had detectable DNA repair mutations were treated with Lynparza.
The objective of the TOPARP-B clinical trial was to determine how effective Lynparza was in men with mutations in any genes known to have a role in repairing DNA – including BRCA1 and 2. All men enrolled in the trial had advanced diseased that had progressed on androgen deprivation therapy, 99% had received Taxotere, 90% Zytiga, Xtandi, and 38% Jevtana.
The researchers initially evaluated the prostate cancers of 592 men and found that 27 per cent had alterations in one or more genes linked to repairing damaged DNA. BRCA mutations were by far the most common mutation and were found in 33 per cent of the cancers with a DNA repair mutation. Other common DNA repair mutations were the genes ATM, CDK12, CHEK2 and PALB2.
After screening and evaluation, they enrolled 98 patients with the DNA repair mutations onto the trial evaluating treatment with Lynparza.
The overall response rate to treatment was 54%. Among 30 men with confirmed mutations in BRCA 1/2 alterations, 83.3% responded to treatment, and 57.1% with PALB2 alterations responded to the treatment. Lynparza delayed cancer progression an average of 5.5 months
- Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England Journal of Medicine. 373:1697-1708. October 29, 2015.